Synthesis and biological activity of novel mono-indole and mono-benzofuran inhibitors of bacterial transcription initiation complex formation

Mielczarek, Marcin; Thomas, Ruth V.; Ma, Cong; Kandemir, Hakan; Yang, Xiao; Bhadbhade, Mohan; Black, David StC.; Griffith, Renate; Lewis, Peter J.; Kumar, Naresh

doi:10.1016/j.bmc.2015.02.037

Cited by 32 publications

(25 citation statements)

References 65 publications

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“…We employed in silico compound screening followed by validation in bacterial cultures and in vitro experiments. A similar methodology has been previously used to identify bacterial transcription inhibitors . Starting from 280 000 compounds spanning many different compound families, 63 compounds were predicted to bind the Specifier Loop and acquired for testing.…”

Section: Discussionmentioning

confidence: 99%

“…As imilar methodology has been previously used to identify bacterial transcription inhibitors. [74,75] Starting from 280 000 compounds spanning many different compound families, 63 compounds werep redicted to bind the Specifier Loop and acquired for testing. From these, PKZ18 was identified as ah it based on the specificity of its antibacterial activity toward Gram-positive bacteria, its inability to induce resistance in multiple bacterial strains,a nd its ability to bind the Specifier Loop construct in vitro.…”

Section: Discussionmentioning

confidence: 99%

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Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

et al. 2019

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The emergence of multidrug‐resistant bacteria necessitates the identification of unique targets of intervention and compounds that inhibit their function. Gram‐positive bacteria use a well‐conserved tRNA‐responsive transcriptional regulatory element in mRNAs, known as the T‐box, to regulate the transcription of multiple operons that control amino acid metabolism. T‐box regulatory elements are found only in the 5′‐untranslated region (UTR) of mRNAs of Gram‐positive bacteria, not Gram‐negative bacteria or the human host. Using the structure of the 5′UTR sequence of the Bacillus subtilis tyrosyl‐tRNA synthetase mRNA T‐box as a model, in silico docking of 305 000 small compounds initially yielded 700 as potential binders that could inhibit the binding of the tRNA ligand. A single family of compounds inhibited the growth of Gram‐positive bacteria, but not Gram‐negative bacteria, including drug‐resistant clinical isolates at minimum inhibitory concentrations (MIC 16–64 μg mL−1). Resistance developed at an extremely low mutational frequency (1.21×10−10). At 4 μg mL−1, the parent compound PKZ18 significantly inhibited in vivo transcription of glycyl‐tRNA synthetase mRNA. PKZ18 also inhibited in vivo translation of the S. aureus threonyl‐tRNA synthetase protein. PKZ18 bound to the Specifier Loop in vitro (Kd≈24 μm). Its core chemistry necessary for antibacterial activity has been identified. These findings support the T‐box regulatory mechanism as a new target for antibiotic discovery that may impede the emergence of resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

et al. 2019

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“…Screening an in-house indole-based peptidomimetic library (N. Kumar, UNSW, Australia) we selected just 9 compounds for further screening of which 5 showed the ability to inhibit HE formation. Although the majority of the peptidomimetic compounds in the in-house library presented here had molecular weights >500 one of the compounds identified in this screen, GKL003, showed excellent in vitro activity [19], and has been derivatised extensively to explore its potential as a future lead molecule [21][22][23].…”

Section: In Silico Screeningmentioning

confidence: 99%

“…When testing compounds for their ability to inhibit the r-b 0 CH interaction, ELISAs were performed as above except the GST tagged wild-type CH-domain fragment (200 nM) was pre-mixed with 15 lM of the test compound at 37°C for 15 min before being added into the r A coated wells [21][22][23]. Compounds showing good levels of inhibition were further tested at a range of concentrations to determine preliminary K i values (Fig.…”

Section: Target Verificationmentioning

confidence: 99%

Identification of inhibitors of bacterial RNA polymerase

Yang

Lewis

2015

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“…Despite having excellent activity in vitro, GKL003 had poor activity against live cultures of bacteria, probably due to its low solubility in aqueous media and inability to cross bacterial membranes. Nevertheless, it did exhibit broad-spectrum antibacterial activity at high concentrations and has been extensively derivatized to establish structure-activity relationships (181)(182)(183). Determination of the structures of GKL compounds in complex with RNAP will be important for their continued development.…”

Section: The Rnap-interactionmentioning

confidence: 99%

Bacterial Transcription as a Target for Antibacterial Drug Development

Yang

Lewis

2016

Microbiol Mol Biol Rev

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113

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SUMMARYTranscription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design.

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Synthesis and biological activity of novel mono-indole and mono-benzofuran inhibitors of bacterial transcription initiation complex formation

Cited by 32 publications

References 65 publications

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

Identification of inhibitors of bacterial RNA polymerase

Bacterial Transcription as a Target for Antibacterial Drug Development

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